DESCRIPTION:(provided by applicant) Sensory neurons that innervate the heart (cardiac afferents) detect cardiac ischemia, the condition when the heart receives insufficient oxygen. They trigger chest pain-either the acute pain of a heart attack or angina, an intermittent pain caused by coronary artery disease. They also contribute to damaging cardiac reflexes that accompany artery disease. Although it is clear that cardiac afferents transduce cardiac pain, the molecular mechanism(s) is uncertain. The driving hypothesis of this proposal is that cardiac ischemia releases a set of chemical mediators that activate ion channels and receptors on cardiac afferents, thereby triggering pain. The proposal relies heavily on a novel method we developed to fluorescently tag cardiac afferents so they can be distinguished from other kinds of sensory neurons. This is an essential step for identifying molecules that are necessary for cardiac pain but not for other sensations. Our initial work fmds that cardiac afferents have a unique molecular fmgerprint: they express an extremely Sensitive acid-sensing ion channel at grossly high levels. The result underscores the importance of protons created during ischemia as a mediator of cardiac pain. Our specific aims will: 1) definitively identify the particular clone of acid-sensing ion channel used by cardiac afferents; 2) fmd whether other putative mediators of cardiac pain act by modulating this channel; 3) explore why there is different expression of channels in the two different populations of cardiac afferents. The experimental methods are single cell electrophysiology and immunocytochemistry. The clinical significance of the project lies in the suppression of angina, which is suffered by some 6 million Americans, is debilitating in some, and which triggers damaging cardiac reflexes in all. The results might also be relevant to other forms of vaso-oclusive pain, notably that of sickle cell anemia. We will identify molecules that trigger cardiac pain, thereby providing new pharmaceutical targets for its treatment.